Macrophage Migration Inhibitory Factor Coordinates DNA Damage Response with the Proteasomal Control of the Cell Cycle

Nemajerová, Alice; Moll, Ute M.; Petrenko, Oleksi; Fingerle-Rowson, Giinter

doi:10.4161/cc.6.9.4163

Cited by 34 publications

(28 citation statements)

References 54 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because serum MIF protein levels correlate with disease state in a variety of cancers (22,23), we first examined MIF expression in the serum of individuals with and without colorectal cancer. MIF levels were lowest in the serum from healthy volunteers with normal colorectal mucosa and increased progressively in patients with colorectal adenoma (P < 0.05) and those with colorectal carcinoma (P < 0.001) (Figure 1).…”

Section: Increased Serum Mif Concentrations Correlated With Colorectamentioning

confidence: 99%

Macrophage Migration Inhibitory Factor Promotes Colorectal Cancer

Chen

Yang

et al. 2009

Mol Med

View full text Add to dashboard Cite

A growing body of evidence implicates macrophage migration inhibitory factor (MIF) in tumorigenesis and metastasis. In this study, we investigated whether MIF expression was associated with clinicopathologic features of colorectal carcinoma (CRC), especially in tumors with hepatic metastasis, and whether neutralization of endogenous MIF using anti-MIF therapeutics would inhibit tumor growth and/or decrease the frequency of colorectal hepatic metastases in a mouse colon carcinoma model. The concentration of serum MIF was positively correlated with an increased risk of hepatic metastasis in human patients with CRC (R = 1.25, 95% confidence internal = 1.02-1.52, P = 0.03). MIF was also dramatically upregulated in human colorectal tissue, with 20-40 times as many MIF-positive cells found in the mucosa of patients with CRC than in normal tissue (P < 0.001 ANOVA). Moreover, in those patients with metastatic colorectal cancer in the liver, MIF-positive cells were similarly increased in the diseased hepatic tissue. This increased MIF expression was restricted to diseased tissue and not found in areas of the liver with normal morphology. In subsequent in vitro experiments, we found that addition of recombinant MIF to colonic cell lines significantly increased their invasive properties and the expression of several genes (for example, matrix metalloproteinase 9 and vascular endothelial growth factor) known to be upregulated in cancerous tissue. Finally, we treated mice that had been given CT26 colon carcinoma cell transplants with anti-MIF therapeutics-either the MIF-specific inhibitor ISO-1 or neutralizing anti-MIF antibodies-and observed a significant reduction in tumor burden relative to vehicle-treated animals. Taken together, these data demonstrate that MIF expression was not only correlated with the presence of colorectal cancer but also may play a direct role in cancer development.

show abstract

Section: Increased Serum Mif Concentrations Correlated With Colorectamentioning

confidence: 99%

Macrophage Migration Inhibitory Factor Promotes Colorectal Cancer

Chen

Yang

et al. 2009

Mol Med

View full text Add to dashboard Cite

show abstract

“…For example, MIF can inhibit the immune regulatory transcription factor AP-1 (23) and downregulates p53 and p53-associated signaling pathways (17,37). Furthermore, MIF is able to regulate cell division and is necessary for normal progression of the cell cycle (33). MIF further distinguishes itself from other cytokines by concurrently possessing enzymatic capabilities.…”

mentioning

confidence: 99%

Plasmodium yoelii Macrophage Migration Inhibitory Factor Is Necessary for Efficient Liver-Stage Development

et al. 2012

View full text Add to dashboard Cite

bMammalian macrophage migration inhibitory factor (MIF) is a multifaceted cytokine involved in both extracellular and intracellular functions. Malaria parasites express a MIF homologue that might modulate host immune responses against blood-stage parasites, but the potential importance of MIF against other life cycle stages remains unstudied. In this study, we characterized the MIF homologue of Plasmodium yoelii throughout the life cycle, with emphasis on preerythrocytic stages. P. yoelii MIF (Py-MIF) was expressed in blood-stage parasites and detected at low levels in mosquito salivary gland sporozoites. MIF expression was strong throughout liver-stage development and localized to the cytoplasm of the parasite, with no evidence of release into the host hepatocyte. To examine the importance of Py-MIF for liver-stage development, we generated a Py-mif knockout parasite (P. yoelii ⌬mif). P. yoelii ⌬mif parasites grew normally as asexual erythrocytic-stage parasites and showed normal infection of mosquitoes. In contrast, the P. yoelii ⌬mif strain was attenuated during the liver stage. Mice infected with P. yoelii ⌬mif sporozoites either did not develop blood-stage parasitemia or exhibited a delay in the onset of blood-stage patency. Furthermore, P. yoelii ⌬mif parasites exhibited growth retardation in vivo. Combined, the data indicate that Plasmodium MIF is important for liver-stage development of P. yoelii, during which it is likely to play an intrinsic role in parasite development rather than modulating host immune responses to infection.

show abstract

“…Therefore, what emerges is the picture of a molecular machine that extracts ubiquitinated and abnormal folded proteins from larger protein complexes or membranes and determines their fate by using the N-terminal domain of p97/VCP and the CSN as a hub for substrate-processing cofactors and regulatory enzymes. Because the interaction of p97/VCP with the CSN originated from an interactome screen for the cytokine MIF, our results also suggest that MIF may not only be involved in regulating the deneddylase activity of CSN5 (46), but appears to control the UPS on a much broader scale.…”

Section: Discussionmentioning

confidence: 55%

COP9 Signalosome Interacts ATP-dependently with p97/Valosin-containing Protein (VCP) and Controls the Ubiquitination Status of Proteins Bound to p97/VCP

Çaylı

Klug

Chapiro

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Ubiquitinated proteins can alternatively be delivered directly to the proteasome or via p97/VCP (valosin-containing protein). Whereas the proteasome degrades ubiquitinated proteins, the homohexameric ATPase p97/VCP seems to control the ubiquitination status of recruited substrates. The COP9 signalosome (CSN) is also involved in the ubiquitin/proteasome system (UPS) as exemplified by regulating the neddylation of ubiquitin E3 ligases. Here, we show that p97/VCP colocalizes and directly interacts with subunit 5 of the CSN (CSN5) in vivo and is associated with the entire CSN complex in an ATP-dependent manner. Furthermore, we provide evidence that the CSN and in particular the isopeptidase activity of its subunit CSN5 as well as the associated deubiquitinase USP15 are required for proper processing of polyubiquitinated substrates bound to p97/VCP. Moreover, we show that in addition to NEDD8, CSN5 binds to oligoubiquitin chains in vitro. Therefore, CSN and p97/VCP could form an ATP-dependent complex that resembles the 19 S proteasome regulatory particle and serves as a key mediator between ubiquitination and degradation pathways.Many fundamental cellular functions such as membrane fusion, gene transcription, DNA replication, and repair are controlled by the covalent linkage of ubiquitin (Ub) 5 to substrate proteins (1). Different Ub modifications serve as signaling-dependent regulators of protein interaction networks (2). Substrates that are polyubiquitinated via Lys 48 are recognized by the 19 S regulatory particle of the proteasome that consists of a lid and a base complex. Upon recognition, substrates are unfolded by the base complex and hydrolyzed within the 20 S proteolytic chamber (3).The COP9 signalosome (CSN) plays an essential role as mediator between signaling pathways and downstream mechanisms controlling developmental processes. This involves ubiquitin-dependent protein degradation of key regulatory molecules like the cell cycle inhibitor p27Kip1 , the tumor suppressor p53, and IkB␣. The CSN is a highly conserved complex found in all higher eukaryotes (4). Like the proteasome lid, it contains eight core subunits (CSN1-8), and for each of them exists a paralogous subunit in the proteasome lid. CSN5 (also known as Jab1) and CSN6 possess a MOV34/PAD N-terminal (MPN) domain (5). The MPN domain of CSN5 harbors a metalloprotease motif referred to as the Jab1/MPN domain-associated metallopeptidase (JAMM) motif that regulates the activity of E3 Ub-ligases by deneddylation of the cullin component (6).The chaperone p97 or valosin-containing protein (p97/VCP) has been recognized as another key player within the ubiquitin/ proteasome system (UPS). p97/VCP extracts mono-or oligoubiquitinated substrates from complexes and presents them to the UPS. It is a member of the family of ATPases associated with various cellular activities (AAA ϩ ) and forms a homohexamer. Two AAA cassettes of each monomer build two consecutive stacked rings (D1 and D2 domain) in the hexamer underneath a ring of flexible N-terminal domains (7...

show abstract

Macrophage Migration Inhibitory Factor Coordinates DNA Damage Response with the Proteasomal Control of the Cell Cycle

Cited by 34 publications

References 54 publications

Macrophage Migration Inhibitory Factor Promotes Colorectal Cancer

Macrophage Migration Inhibitory Factor Promotes Colorectal Cancer

Plasmodium yoelii Macrophage Migration Inhibitory Factor Is Necessary for Efficient Liver-Stage Development

COP9 Signalosome Interacts ATP-dependently with p97/Valosin-containing Protein (VCP) and Controls the Ubiquitination Status of Proteins Bound to p97/VCP

Contact Info

Product

Resources

About